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ROTECTING LUNGS FROM VENTIlation-induced injury is an important principle in the management of patients with acute
lung injury or acute respiratory distress
syndrome (ARDS). Although the critical care community has generally endorsed lower tidal volumes and inspiratory pressures, the optimal level of
positive end-expiratory pressure (PEEP)
remains unestablished.1,2 Experimental
data suggest that PEEP levels exceeding traditional values of 5 to 12 cm H2O
can minimize cyclical alveolar collapse
and corresponding shearing injury to the
lungs in patients with considerable
edema and alveolar collapse.3-5 For patients with relatively mild acute lung in-
JAMA. 2010;303(9):865-873
865
The predefined protocol for this metaanalysis of individual-patient data is available from the authors on request. Randomized trials eligible for this review
compared higher with lower levels of
PEEP (mean difference of at least 3 cm
H2O between groups during first 3 days
following randomization) in critically ill
adults (16 years) with a diagnosis of
acute lung injury or ARDS as defined by
the American-European Consensus Conference.12 Eligible trials incorporated a
target tidal volume of less than 8 mL/kg
of predicted body weight in both the experimental and the control ventilation
strategies and provided patient follow-up to death or for at least 20 days.
We identified eligible trials by an
electronic search of MEDLINE,
EMBASE, and the Cochrane Central
Register of Controlled Trials (all from
1996 to January 2010) using the terms
positive end-expiratory pressure*, PEEP,
low tidal volume*, open lung strateg*,
acute respiratory distress, acute lung injur*, and ards as text words and positive pressure respiration, tidal volume,
and respiratory distress syndrome as
Medical Subject Headings. We used a
sensitive filter for randomized controlled trials13 and imposed no lan866
Control intervention
Ventilator procedures
ALVEOLI,8 2004
Acute lung injury with PaO2:FIO2 300 a
1999-2002
23 (United States)
276 vs 273
LOVS,9 2008
Acute lung injury with PaO2:FIO2 250 a
2000-2006
30 (Canada, Australia, Saudi Arabia)
476 vs 509 b
EXPRESS,10 2008
Acute lung injury with PaO2:FIO2 300 a
2002-2005
37 (France)
385 vs 383 c
Yes
100
Yes
100
Yes
100
Yes
Yes
Yes
Stopped for perceived futility
No
Stopped for perceived futility
PEEP as high as possible without increasing
Higher PEEP according to FIO2 chart, recruit- Higher PEEP according to FIO2 chart, rement maneuvers for first 80 patients
quired plateau pressures 40 cm H2O,
the maximum inspiratory plateau presrecruitment maneuvers
sure 28-30 cm H2O
Conventional PEEP according to FIO2 chart, Conventional PEEP according to FIO2 chart, Conventional PEEP (5-9 cm H2O) to meet
required plateau pressures 30 cm H2O,
required plateau pressures 30 cm H2O,
oxygenation goals
no recruitment maneuvers
no recruitment maneuvers
Target tidal volumes of 6 mL/kg of predicted body weight; plateau pressures 30 cm H2O (with exception as above); respiratory rate 35/
min, adjusted to achieve arterial pH 7.30-7.45; ventilator mode: volume-assist control (except higher PEEP group in LOVS required
pressure control); oxygenation goals: PaO2 55-80 mm Hg and SPO2 88%-95%; standardized weaning)
Abbreviations: ALVEOLI, Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury; EXPRESS, Expiratory Pressure Study; FIO2, fraction of inspired
oxygen; LOVS, Lung Open Ventilation to Decrease Mortality in the Acute Respiratory Distress Syndrome; PEEP, positive end-expiratory pressure; SPO2, oxygen saturation.
a Acute lung injury defined according to the American-European Consensus Conference.12
b Includes 2 patients for whom consent was withdrawn prior to protocol initiation, without patient, family, and caregivers being aware of group assignment (ie, 983 patients analyzed).
c Includes 1 patient for whom consent was withdrawn prior to protocol initiation, without patient, family, and caregiver awareness of assignment (ie, 767 patients included in the analysis).
867
RESULTS
Three trials, including 2299 patients, met
our eligibility criteria (FIGURE 1). In the
Assessment of Low Tidal Volume and
Elevated End-Expiratory Pressure to
Obviate Lung Injury (ALVEOLI) trial
(NCT00000579)8 and the Lung Open
Ventilation to Decrease Mortality in the
Acute Respiratory Distress Syndrome
(LOVS) study (NCT00182195), 9
PEEP levels were titrated to oxygenation using similar PEEP:FIO2 charts
(TABLE 1). The experimental strategy
in the Expiratory Pressure Study
(EXPRESS) (NCT00188058) 1 0 titrated PEEP levels based on measurements of plateau pressure, regardless of
the effect on oxygenation. Control strategies were similar in the ALVEOLI and
LOVS studies, which allowed appre-
567 (50)
214 (19)
595 (52)
71 (6.3)
37 (3.3)
60 (5.3)
146 (13)
578 (50)
247 (21)
628 (54)
74 (6.4)
48 (4.1)
73 (6.3)
119 (10)
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit; IQR, interquartile range; PEEP, positive end-expiratory pressure; SAPS II,
Simplified Acute Physiology Score II.
a Calculated as weight in kilograms divided by height in meters squared.
b Dichotomized Brussels Score as used in the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury study;22 circulatory failure was defined
as systolic blood pressure of 90 mm Hg or less or the need for treatment with any vasopressor; coagulation failure as platelet count of 50 000 platelets/mm3 or less; hepatic failure
as serum bilirubin concentration greater than 5.9 mg/dL (100 mol/L); renal failure as serum creatinine concentration greater than 3.4 mg/dL (300 mol/L); and neurologic failure
as Glasgow Coma Scale score of 9 or less.
c Includes altitude adjustment for patients from Colorado ([760/635]PaO :FIO2) and Utah ([760/642]PaO :FIO ); for 25 ALVEOLI patients with missing PaO :FIO values at ven2
2
2
2
2
tilation change, PaO2:FIO2 values from the screening form of the same day were used.
d Oxygenation index was calculated as mean airway pressure100/(PaO :FIO ).
2
2
e Respiratory system compliance was calculated as tidal volume/(inspiratory plateau pressurePEEP).
f Individual patients could have more than 1 cause of lung injury.
g Includes drug overdose, prolonged shock, burn injury, inhalation injury, intra-alveolar hemorrhage, cardiopulmonary bypass, near drowning, vasculitis, and heat stroke.
868
and lower PEEP groups was not statistically significant (32.9% vs 35.2%; RR,
0.94; 95% CI, 0.86-1.04; P=.25). However, we found a statistically significant reduction of death in the intensive care unit for patients allocated to
the higher PEEP group (28.5% vs
32.8%; RR, 0.87; 95% CI, 0.78-0.97;
P = .01). Clinicians instituted rescue
therapies for profound hypoxemia less
frequently in patients with higher PEEP,
and the rate of deaths following rescue therapy was also significantly lower.
The groups did not differ significantly
in rates of pneumothorax, hospital
deaths following pneumothorax, use of
vasopressors, or number of days with
unassisted breathing during the first 28
days of study.
For patients with ARDS at baseline,
those in the higher PEEP group were
less likely to die in hospital (34.1% vs
39.1%; RR, 0.90; 95% CI, 0.81-1.00;
P=.049) and more likely to achieve unassisted breathing earlier (hazard ratio, 1.16; 95% CI, 1.03-1.30; P=.01; proportions at 28 days, 64.3% vs 57.8%);
for patients without ARDS at baseline,
the RR for death in hospital with higher
vs lower PEEP was 1.37 (95% CI, 0.981.92; P=.07; 27.2% vs 19.4%) and the
hazard ratio for time to unassisted
breathing was 0.79 (95% CI, 0.62-
Day 3
Day 7
Higher
PEEP
Lower
PEEP
P
Value
Higher
PEEP
Lower
PEEP
P
Value
Higher
PEEP
Lower
PEEP
P
Value
6.3 (1.0)
[n = 1051]
6.3 (0.8)
[n = 1051]
.33
6.3 (1.0)
[n = 793]
6.3 (1.0)
[n = 852]
.47
6.5 (1.4)
[n = 443]
6.4 (1.3)
[n = 494]
.25
29 (5.4)
[n = 1043]
23 (5.6)
[n = 991]
.001
27 (5.6)
[n = 781]
23 (5.9)
[n = 825]
.001
27 (6.2)
[n = 408]
24 (6.9)
[n = 443]
.001
FIO2
0.51 (0.18)
[n = 1053]
0.61 (0.19)
[n = 1051]
.001
0.44 (0.15)
[n = 812]
0.56 (0.18)
[n = 862]
.001
0.45 (0.15)
[n = 502]
0.54 (0.19)
[n = 550]
.001
PEEP, cm H2O
15.3 (3.4)
[n = 1053]
9.0 (3.1)
[n = 1051]
.001
13.3 (4.3)
[n = 812]
8.2 (3.0)
[n = 863]
.001
10.8 (5.0)
[n = 503]
7.8 (3.3)
[n = 548]
.001
Oxygenation index a
13.2 (8.7)
[n = 949]
12.7 (7.8)
[n = 944]
.16
11.2 (7.0)
[n = 705]
11.6 (7.1)
[n = 755]
.29
11.2 (7.1)
[n = 392]
11.8 (8.4)
[n = 421]
.34
PaO2, mm Hg
96 (38)
[n = 1024]
83 (29)
[n = 1026]
.001
87 (31)
[n = 792]
82 (28)
[n = 835]
.001
84 (25)
[n = 484]
83 (26)
[n = 532]
.41
PaCO2, mm Hg
44 (11)
[n = 1025]
44 (11)
[n = 1026]
.42
44 (9.9)
[n = 792]
44 (11)
[n = 835]
.68
45 (12)
[n = 485]
46 (12)
[n = 532]
.06
Arterial pH
7.35 (0.09)
[n = 1025]
7.36 (0.09)
[n = 1026]
.02
7.38 (0.08)
[n = 793]
7.38 (0.08)
[n = 836]
.49
7.41 (0.08)
[n = 485]
7.40 (0.08)
[n = 532]
.08
Variable
869
ference, 1.6%) with higher PEEP, but differences in fatal consequences from such
barotrauma are unlikely (absolute risk
difference, 0.6%; RR, 1.20; 95% CI, 0.791.81). Otherwise, we found no evidence suggesting serious adverse effects associated with higher PEEP in
patients with ARDS.
The strengths of this review include
an explicit study protocol and analysis
plan; access to trial protocols, case report forms, and complete, unedited data
sets; standardized outcome definitions
across trials (except for rescue therapies); and analyses based on the intention-to-treat principle. To minimize the
risk of overfitting and data-driven associations, we prespecified a limited number of prognostic factors and potential
effect modifiers for our statistical models.23 We calculated RRs adjusted for im-
Table 4. Clinical Outcomes in All Patients and Stratified by Presence of ARDS at Baseline
All Patients
With ARDS
No. (%)
Outcomes
Higher
Lower
PEEP
PEEP
(n = 1136) (n = 1163)
Without ARDS
No. (%)
Higher
Adjusted RR
P
PEEP
a
(95% CI)
Value (n = 951)
Lower
PEEP
(n = 941)
No. (%)
Higher
Lower
Adjusted RR
P
PEEP
PEEP
a
(95% CI)
Value (n = 184) (n = 220)
Adjusted RR
P
(95% CI) a
Value
Death in hospital
0.94
(0.86 to 1.04)
.25
0.90
(0.81 to 1.00)
1.37
(0.98 to 1.92)
.07
Death in ICU b
0.87
(0.78 to 0.97)
.01
0.85
(0.76 to 0.95)
1.07
(0.74 to 1.55)
.71
87 (7.7)
75 (6.5)
1.19
(0.89 to 1.60)
.24
80 (8.4)
64 (6.8)
1.25
(0.94 to 1.68)
.13
7 (3.8)
11 (5.0)
0.72
(0.37 to 1.39)
.33
43 (3.8)
Death after
pneumothorax c
40 (3.5)
1.11
(0.73 to 1.69)
.63
41 (4.3)
35 (3.7)
1.20
(0.79 to 1.81)
.39
2 (1.1)
5 (2.3)
0.44
(0.08 to 2.35) g
.34
.10
12 (0-21)
1.22
(0.39 to 2.05) e
1.74
(3.60 to 0.11) e
.07
Pneumothorax
between day
1 and day 28 c
13 (0 to 22) 11 (0 to 21)
0.64
Days with
(0.12 to 1.39) e
unassisted
breathing
between day 1
and day 28,
median (IQR) d
Total use of rescue 138 (12.2) 216 (18.6)
therapiesf
Death after rescue
therapy f
Use of
vasopressors
85 (7.5)
132 (11.3)
7 (0-20)
0.64
.001 130 (13.7) 200 (21.3)
(0.54 to 0.75)
0.63
.001
(0.53 to 0.75)
8 (4.4)
16 (7.3)
0.60
(0.25 to 1.43) g
.25
0.65
.001
(0.52 to 0.80)
0.66
.001
(0.52 to 0.82)
3 (1.6)
8 (3.6)
0.37
(0.10 to 1.46) g
.15
0.92
(0.56 to 1.50) g
.72
0.93
(0.75 to 1.14) g
.49
82 (8.6)
124 (13.2)
0.90
(0.72 to 1.13) g
.37
Abbreviations: ARDS, acute respiratory distress syndrome; CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; PEEP, positive end-expiratory pressure; RR,
relative risk.
a Multivariable regression with the outcome of interest as dependent variable; PEEP group, age, probability of dying in hospital derived from prognostic scores at baseline, severe
sepsis at baseline, and trial as independent variables; and hospital as a random effect.
b Patients who died before being discharged from the intensive care unit for the first time up to day 60.
c Defined as the need for chest tube drainage.
d Median number of days of unassisted breathing to day 28 after randomization, assuming a patient survives and remains free of assisted breathing for at least 2 consecutive
calendar days after initiation of unassisted breathing.
e Coefficient from a corresponding linear regression model using the same independent variables and random effect as the above-described log-binomial model; for example, a
coefficient of 1.22 means that patients in the group treated with higher PEEP have, on average, 1.22 days more of unassisted breathing during the first 28 days compared with
patients in the group treated with lower PEEP.
f As defined in each trial; rescue therapies included in the Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury and the Lung Open Ventilation to Decrease Mortality in the Acute Respiratory Distress Syndrome studies: inhaled nitric oxide, prone ventilation, high-frequency oscillation, high-frequency jet ventilation,
extracorporeal membrane oxygenation, partial liquid ventilation, and surfactant therapy. Rescue therapies included in the Expiratory Pressure Study: prone ventilation, inhaled
nitric oxide, and almitrine bismesylate.
g Adjusted odds ratio substitutes for relative risk, because the corresponding log-binomial model did not converge.
870
Figure 2. Time to Death in Hospital and Time to Unassisted Breathing for Higher and Lower
Positive End-Expiratory Pressure (PEEP) Stratified by Presence of Acute Respiratory Distress
Syndrome (ARDS) at Baseline
In-hospital time to death
Patients with ARDS
1.0
Probability
0.8
0.6
HR, 1.32 (95% CI, 0.87-2.00); P = .20
0.2
0
0
20
40
60
760
723
693
649
20
40
60
183
219
158
196
148
186
144
183
1.0
HR, 1.16 (95% CI, 1.03-1.30); P = .01
0.8
Probability
0.6
0.4
0.2
HR, 0.79 (95% CI, 0.62-0.99); P = .04
0
0
14
21
28
653
589
408
328
283
207
14
21
28
183
219
145
179
95
123
60
83
44
63
Cox regression models adjusting for age, probability of death in hospital derived from prognostic scores at baseline, severe sepsis at baseline, and trial. For the analysis of time to unassisted breathing, data were censored at the
time of death because time to death was modeled separately and a sensitivity analysis without censoring at death
yielded very similar results. Additionally including the Esophageal Pressure Directed Ventilation trial (n=61) revealed adjusted hazard ratios (HRs) for hospital mortality of 0.83 (95% confidence interval [CI], 0.71-0.96; P=.01;
33.9% vs 39.0%) for patients with ARDS (n=1941) and 1.26 (95% CI, 0.84-1.88; P=.27; 26.5% vs 19.4%) for
patients without ARDS (n=416). Corresponding hazard ratios for time to unassisted breathing were 1.14 (95%
CI, 1.02-1.28; P=.02; proportions at 28 days, 64.2% vs 58.0%) for patients with ARDS (n=1941) and 0.80 (95%
CI, 0.64-1.01; P=.06; proportions at 28 days, 70.4% vs 79.7%) for patients without ARDS (n=416).
871
precision of this finding (individual subgroup P=.02). The wide CI around the
estimated RR of mortality in patients
without ARDS warrants a rating of moderate-quality evidence.
Without considering the subgroup
analysis definitive, and while awaiting
further evidence on the topic, our results may have the following clinical implications. The potentially lower hospital mortality and the absence of increased
serious adverse events associated with
higher PEEP levels in patients with ARDS
support the safety of higher PEEP in
these patients. For this purpose, clinicians could titrate PEEP as described in
the 3 major trials in this review (eAppendix). For patients without ARDS, the
results lack statistical power; still, the
95% CI of 0.98-1.92 for hospital mortality in patients without ARDS indicates that an RR reduction of 2% (0.4%
absolute reduction) associated with
higher PEEP is plausible but that larger,
important risk reductions are unlikely.
Clinicians should bear in mind the possible harm when considering the use of
higher PEEP in patients with less severe acute lung injury.
In addition to its clinical messages,
our work provides lessons for clinical
trialists. Single trials, even those powered for moderate effects, will often
fail to provide definitive answers.
Such trials will almost invariably be
unable to meaningfully address possible subgroup effects. A culture of
international collaboration, ideally
using coordinated trial protocols and
conducting prospective meta-analysis
of individual-patient data, is required
to maximize the clinical information
from expensive and arduous clinical
trials. With a view to ultimately using
individual trial data to contribute to
such a larger effort, investigators
should also keep this option in mind
when they consider stopping trials
early for futility.37
In summary, this systematic review
and meta-analysis of individualpatient data suggests that higher levels of PEEP may be associated with
lower hospital mortality in patients
meeting criteria for ARDS. Our results
further suggest that such a benefit is unlikely in patients with less severe lung
injury; indeed, a strategy of treating
these patients using high PEEP levels
may be harmful.
Author Affiliations: Departments of Clinical Epidemiology and Biostatistics (Drs Briel, Meade, Walter, Pullenayegum, Zhou, Cook, Lamontagne, and Guyatt and
Ms Bhatnagar) and Medicine (Drs Meade and Guyatt), McMaster University, Hamilton, Ontario, Canada;
Basel Institute for Clinical Epidemiology, University Hospital Basel, Basel, Switzerland (Dr Briel); University Hospital Angers, Angers, France (Dr Mercat); Division of Pulmonary and Critical Care Medicine, Johns Hopkins
University, Baltimore, Maryland (Dr Brower); Department of Anesthesia, Critical Care, and Pain Medicine,
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (Dr Talmor); University of Toronto, Toronto, Ontario, Canada (Drs Slutsky
and Stewart); Medical ICU, University Hospital Albert
ChenevierHenri Mondor, INSERM Unit 955 and University Paris-Est, Creteil, France (Dr Brochard); University Hospital Charles Nicolle and UPRES EA Unit 3830,
Rouen, France (Dr Richard); and University of Sherbrooke, Sherbrooke, Quebec, Canada (Dr Lamontagne).
Author Contributions: Dr Briel had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Briel, Meade, Mercat,
Slutsky, Brochard, Lamontagne, Guyatt.
Acquisition of data: Briel, Meade, Mercat, Brower,
Talmor, Slutsky, Brochard, Richard, Bhatnagar, Guyatt.
Analysis and interpretation of data: Briel, Meade,
Brower, Walter, Pullenayegum, Zhou, Cook, Brochard,
Stewart, Guyatt.
Drafting of the manuscript: Briel, Meade, Walter,
Guyatt.
Critical revision of the manuscript for important intellectual content: Meade, Mercat, Brower, Talmor,
Slutsky, Pullenayegum, Zhou, Cook, Brochard, Richard,
Lamontagne, Bhatnagar, Stewart.
Statistical analysis: Briel, Walter, Pullenayegum, Zhou.
Obtained funding: Briel, Meade, Guyatt.
Administrative, technical, or material support: Briel,
Brower, Cook, Bhatnagar, Stewart.
Study supervision: Briel, Meade, Guyatt.
Financial Disclosures: Dr Mercat and Dr Richard reported receiving a research grant from General Electric. Dr Slutsky reported receiving consulting fees from
Maquet Medical. Dr Brochard reported that his research laboratory has received research grants for the
conduct of clinical trials during 2006, 2007, and 2008
from Drger, General Electric, Maquet, Viasys, and
Starmed. No other authors reported financial disclosures.
Funding/Support: The study was funded in part by a
grant from the Canadian Intensive Care Foundation.
Dr Briel is supported by a scholarship from the Swiss
National Science Foundation (PASMA-112951/1) and
the Roche Research Foundation. Dr Cook is a Canada
Research Chair of the Canadian Institutes for Health
Research.
Role of the Sponsor: The funding sources had no role
in the design and conduct of the study; the collection, analysis and interpretation of the data; or the
preparation, review, or approval of the manuscript.
Online-Only Material: eTables 1 through 5, eFigures 1 and 2, and the eAppendix are available at http:
//www.jama.com.
Additional Contributions: We thank Jean Marie Chretien, MSc (Centre Hospitalier Universitaire dAngers,
Angers, France), David Schoenfeld, PhD, and Katherine Husk, BSc (both of Massachusetts General Hospital, Boston), for assisting with data queries. We are
grateful to Ramon Saccilotto, MD (Basel Institute for
REFERENCES
1. Gattinoni L, Caironi P. Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA. 2008;299(6):691-693.
2. Dellinger RP, Levy MM, Carlet JM, et al; International Surviving Sepsis Campaign Guidelines
Committee; American Association of Critical-Care
Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of
Intensive Care Medicine; European Respiratory Society;
International Sepsis Forum; Japanese Association for
Acute Medicine; Japanese Society of Intensive Care
Medicine; Society of Critical Care Medicine; Society
of Hospital Medicine; Surgical Infection Society; World
Federation of Societies of Intensive and Critical Care
Medicine. Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296327.
3. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir
Crit Care Med. 1998;157(1):294-323.
4. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):17751786.
5. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal
ventilation at low airway pressures can augment lung
injury. Am J Respir Crit Care Med. 1994;149(5):
1327-1334.
6. Pinsky MR. The hemodynamic consequences of mechanical ventilation: an evolving story. Intensive Care
Med. 1997;23(5):493-503.
7. Kumar A, Pontoppidan H, Falke KJ, Wilson RS, Laver
MB. Pulmonary barotrauma during mechanical
ventilation. Crit Care Med. 1973;1(4):181-186.
8. Brower RG, Lanken PN, MacIntyre N, et al; National Heart, Lung, and Blood Institute ARDS Clinical
Trials Network. Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;
351(4):327-336.
9. Meade MO, Cook DJ, Guyatt GH, et al; Lung Open
Ventilation Study Investigators. Ventilation strategy
using low tidal volumes, recruitment maneuvers, and
high positive end-expiratory pressure for acute lung
injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637645.
10. Mercat A, Richard JC, Vielle B, et al; Expiratory
Pressure (Express) Study Group. Positive end-
873